Study points to markers for Novartis Fragile X drug

LONDON (Reuters) - A "fingerprint" on a key gene in certain people with a mental retardation condition called Fragile X syndrome may act as a marker for patients who could benefit from an experimental Novartis drug.

The drug, called AFQ056, is designed to reduce the activity of a protein called mGluR5 in the brain and data published on Wednesday from an early trial of 30 Fragile X patients showed that it helped improve symptoms in some, but not all of them.

Researchers who led the study said an analysis of those Fragile X patients who did respond showed they have a kind of "fingerprint" in their DNA that marks them out. They now plan larger trials to see if the findings can be confirmed.

"These are very early-stage data... from a study with a small sample size and we are in the process of doing further studies to see if we can validate these markers," said Baltazar Gomez-Mancilla of the Novartis Institutes for Biomedical Research, whose work is scheduled to be published in the Science Translational Medicine journal on Wednesday.

"This could open a new way to look at drug response."

Fragile X is the most common cause of inherited mental retardation and affects one in every 5,000 children worldwide.

It is caused by a mutation in a single gene, known as Fragile X Mental Retardation-1, or FMR1, where part of the gene is made longer than normal by additional repeats of DNA sequence, the researchers explained in their study.

The degree of gene elongation varies from person to person -- some people have only a small expansion and do not show any symptoms of Fragile X, while others have much more expansion, known as full mutation. In people with full mutation, the FMR1 gene is shut down, resulting in severe Fragile X symptoms and abnormal development of connections in the brain.

Normally, the FMR protein keeps the mGluR5 protein in check. mGluR5 belongs to a family of proteins called mGlu5 receptors that are essential for many aspects of normal brain function. But in patients with Fragile X, the FMR protein is missing, making the mGluR5 overactive in the brain and, in turn, leading to symptoms of Fragile X.

The research team, led by Sebastien Jacquemont of Vaudois University in Switzerland, ran a set of tests designed to detect changes in behaviors like hyperactivity and inappropriate speech in the patients.

While the AFQ056 drug had no effect significant effect on behavior in an initial series of tests, it did show an effect when a subset of the patients was analyzed and compared to a group of patients given a placebo, or dummy, treatment.

In an analysis of this subset of patients, Jacquemont's team found that the promoter of the FMR1 gene -- the control switch that interacts with DNA to turn on gene activity -- was "fully methylated", or fully shut down.

Methylation is a chemical alteration that controls how active a gene is. Methylation status of genes can show up in blood tests and Gomez-Mancilla said this may provide a possible signature of people with Fragile X who could benefit from mGluR5-blocking drugs.

"This correlation between response to treatment and methylation status of the FMR1 promoter sets the stage for future studies designed to test whether methylation can serve as a predictor of positive drug response in patients with Fragile X syndrome," the researchers wrote.